HDAC INHIBITORS AGAINST CANCERS

by Selleckchem | Aug 15 2012

HDAC INHIBITION AND EPIGENETIC MODULATION
An important process; histone acetylation is related to cellular functions for example cell death and cell growth stimulating the protein transcription inhibition by removing the acetyl groups from the related proteins hence causing the increase in DNA binding and making it more condensed. Any disturbance in this process leads to the uncontrolled cellular growth that further leads to the tumor production and also the neurodegenerative diseases. Histone deacetylase inhibition is carried out for the treatment of different types of tumors by using the HDAC-6 inhibitors. Various successful studies at different levels have exhibited the mode of action of histone deacetylase inhibitors further leading to their vast area of applications in different clinical and pre-clinical studies [1]. The HDAC inhibitors levels can be analyzed by using various types of assays specifically developed for this purpose [2]. These assays can be carried out in the labs through different kits. Researchers can perform microplate reader compatible assay and the nonisotopic HDAC inhibitor assay and also the one for compound profiling and robotic screening [4]. In addition to this simple flourogenic assay may also be carried out for the process of high-throughput screening [5].

FAMOUS HDAC INHIBITORS:
Long time before the association between the cancer and tumor formation was described that has led to the idea of selective inhibitors of histone deacetylases used as a good potential approach for the cancer therapy [6]. There are enormous numbers of HDAC inhibitor molecules out of which the most famous are as follows: SAHA or Panobinostat, Entinostat, Belinostat, Romidepsin and CUDC101. A person for his research uses can easily get these drugs from their respective suppliers. These HDAC inhibiting drugs are also in use as anti-epileptics for the epilepsy patients having different kinds of neurological and psychiatric issues and also a mood stabilizer. Among these inhibitor molecules many are still at their developmental stages but many are at successful clinical levels. Along with the treatment of different types of cancers, the HDAC-7 inhibitors are also involved in the treatment of some neurodegenerative diseases [7].

CLINICAL STUDIES OF HDAC INHIBITORS:
Panobinostat, in the phase I and phase II of clinical trials, was used for treating the patients of -cell lymphoma and exhibited very remarkable results [8]. Belinostat, in phase II clinical studies, was also proved to a potent drug against advanced malignant pleural mesothelioma exhibiting very little disease stabilization and side effects in the patients [9]. CUDC-101 that is a multi tyrosine kinase inhibitor also gave good results by affecting on HER2, EGFR and HDAC leading to the inhibited cancerous growth [10]. Another eminent example of HDAC inhibitor is Valproate that is now undergoing the clinical trials and found to be very potent chemical drug against tumor cell growth and also stimulates the apoptotic cell death during the clinical studies of the cervical cancer. Vorinostat is the most famous and leading HDAC inhibiting drug that gained the very first approval from FDA or Food and Drug administration. Entinostat is under clinical trials these days for the treatment of breast cancer, Hodgkin’s lymphoma and metastatic lung cancer.

REFERENCES:
1. Iglesias OM, e.a., Histone deacetylase inhibitors: mechanism of action and therapeutic use in cancer. Clinical and Translational Oncology, 2008.
2. Yuan Z, e.a., Histone Deacetylase Activity Assay Methods in Molecular Biology, 2009.
3. Heltweg B, J.M., A Microplate Reader-Based Nonisotopic Histone Deacetylase Activity Assay. Analytical Biochemistry, 2002.
4. Ciossek T, e.a., A homogeneous cellular histone deacetylase assay suitable for compound profiling and robotic screening. Analytical Biochemistry, 2008.
5. Wegener D, e.a., A fluorogenic histone deacetylase assay well suited for high-throughput activity screening. Chem Biol., 2003.
6. Richon VM, a.O.B.J., Histone Deacetylase Inhibitors: A New Class of Potential Therapeutic Agents for Cancer Treatment. Clin. Cancer Res, 2002.
7. Chuang DM, e.a., Multiple roles of HDAC inhibition in neurodegenerative conditions. Trends in Neurosciences, 2009.
8. Prince HM, B.M., Panobinostat (LBH589): a novel pan-deacetylase inhibitor with activity in T cell lymphoma. Hematology Meeting Reports, 2009.
9. Ramalingam SS, e.a., Phase II study of belinostat (PXD101), a histone deacetylase inhibitor, for second line therapy of advanced malignant pleural mesothelioma. J Thorac Oncol., 2009.
10. Lai CJ, e.a., CUDC-101, a Multitargeted Inhibitor of Histone Deacetylase, Epidermal Growth Factor Receptor, and Human Epidermal Growth Factor Receptor 2, Exerts Potent Anticancer Activity. Cancer Res, 2010.
11. Blanco AC, e.a., Histone acetylation and histone deacetylase activity of magnesium valproate in tumor and peripheral blood of patients with cervical cancer. A phase I study. Molecular Cancer, 2005.

Cat.No.	Product Name	Information
S1030	Panobinostat (LBH589)	Panobinostat (LBH589, NVP-LBH589) is a novel broad-spectrum HDAC inhibitor with IC50 of 5 nM in a cell-free assay. Panobinostat (LBH589) induces autophagy and apoptosis. Panobinostat effectively disrupts HIV latency in vivo. Phase 3.
S1053	Entinostat (MS-275)	Entinostat (MS-275, SNDX-275) strongly inhibits HDAC1 and HDAC3 with IC50 of 0.51 μM and 1.7 μM in cell-free assays, compared with HDACs 4, 6, 8, and 10. Entinostat induces autophagy and apoptosis. Phase 3.
S1085	Belinostat	Belinostat is a novel HDAC inhibitor with IC50 of 27 nM in a cell-free assay, with activity demonstrated in cisplatin-resistant tumors. Belinostat (PXD101) induces autophagy.
S3020	Romidepsin	Romidepsin (FK228, Depsipeptide, FR 901228, NSC 630176) is a potent HDAC1 and HDAC2 inhibitor with IC50 of 36 nM and 47 nM in cell-free assays, respectively. Romidepsin (FK228/depsipeptide) controls growth and induces apoptosis in neuroblastoma tumor cells.
S1194	CUDC-101	CUDC-101 is a potent multi-targeted inhibitor against HDAC, EGFR and HER2 with IC50 of 4.4 nM, 2.4 nM, and 15.7 nM, and inhibits class I/II HDACs, but not class III, Sir-type HDACs. Phase 1.